Lymphotoxin/LIGHT in Lipoprotein Metabolism and Atherosclerosis

淋巴毒素/光在脂蛋白代谢和动脉粥样硬化中的作用

• 批准号: 7133991
• 负责人: GODFREY Shalom GETZ
• 金额: $ 37.25万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7133991
• 关键词: apolipoprotein E; atherosclerosis; atherosclerotic plaque; biological signal transduction; blood circulation; gene expression; genetically modified animals; insulin sensitivity /resistance; laboratory mouse; ligands; lipid metabolism; low density lipoprotein; low density lipoprotein receptor; receptor expression; tumor necrosis factor beta

DESCRIPTION (provided by applicant): Atherosclerosis is a chronic inflammatory reaction involving both the innate and adaptive immune system. The activation of the adaptive immune system requires the primary stimulus along with the ligation of costimulatory ligands and receptors. LIGHT/lymphotoxin is one set of costimulatory ligands. Signaling by these ligands is shown here to affect lipoprotein metabolism and atherosclerosis. Members of this family of ligands and receptors are expressed by immune cells that either have been shown to or are thought to influence the development of atherosclerosis as well as on non-immune cells such as hepatocytes. We have observed that manipulation of LIGHT/lymphotoxin and signaling through their receptors exert profound effects on plasma lipoproteins, yet these effects may be counterbalanced at the level of the vascular wall perhaps by effects on local vascular inflammation. Blocking LIGHT/lymphotoxin signaling in LDL receptor deficient mice using a soluble lymphotoxin beta receptor significantly decreased VLDL levels, but had no effect on the size of the aortic root lesion. LIGHT over expression in T-cells in LDL receptor deficient mice resulted in the accumulation of a small LDL, and a reduction in the size of the aortic root lesion. We propose three specific aims dealing with VLDL (aim 1), LDL (aim 2) and atherosclerosis (aim 3) following manipulation of LIGHT/lymphotoxin signaling. Specific aim 1 will examine the mechanism by which interfering with LIGHT/lymphotoxin influences VLDL metabolism, and whether this effect is mediated by LIGHT or lymphotoxin alpha1beta2, and the potential role of apoE. Specific aim 2 will examine the mechanism by which over expression of LIGHT influences LDL heterogeneity, including if insulin resistance has a role. The final aim will examine the role of this family of ligands on atherosclerosis, including if the LIGHT/lymphotoxin family influences plaque stability. The goal of this proposal is to understand how the LIGHT/lymphotoxin ligand family influences lipoprotein homeostasis and atherosclerosis. These studies will further our understanding of how the immune system influences these processes and may point to potential sites for therapeutic intervention.

描述（由申请人提供）：动脉粥样硬化是一种涉及先天性和适应性免疫系统的慢性炎症反应。适应性免疫系统的激活需要初始刺激以及共刺激配体和受体的连接。光/淋巴毒素是一组共刺激配体。这里显示这些配体的信号传导会影响脂蛋白代谢和动脉粥样硬化。该配体和受体家族的成员由免疫细胞表达，这些免疫细胞已被证明或被认为影响动脉粥样硬化的发展，以及肝细胞等非免疫细胞。我们观察到，光/淋巴毒素的操纵和通过其受体的信号传导对血浆脂蛋白产生深远的影响，但这些影响可能在血管壁水平上通过对局部血管炎症的影响而被抵消。使用可溶性淋巴毒素β受体阻断LDL受体缺陷小鼠中的LIGHT/淋巴毒素信号传导可显着降低VLDL水平，但对主动脉根部病变的大小没有影响。 LDL 受体缺陷小鼠的 T 细胞中 LIGHT 过度表达导致少量 LDL 的积累，并缩小主动脉根部病变的大小。我们提出了在操纵光/淋巴毒素信号传导后处理 VLDL（目标 1）、LDL（目标 2）和动脉粥样硬化（目标 3）的三个具体目标。具体目标 1 将研究干扰 LIGHT/淋巴毒素影响 VLDL 代谢的机制，以及这种效应是否由 LIGHT 或淋巴毒素 α1β2 介导，以及 apoE 的潜在作用。具体目标 2 将研究 LIGHT 过度表达影响 LDL 异质性的机制，包括胰岛素抵抗是否发挥作用。最终目标是检查该配体家族对动脉粥样硬化的作用，包括 LIGHT/淋巴毒素家族是否影响斑块稳定性。 该提案的目的是了解 LIGHT/淋巴毒素配体家族如何影响脂蛋白稳态和动脉粥样硬化。这些研究将进一步加深我们对免疫系统如何影响这些过程的理解，并可能指出治疗干预的潜在位点。